The widened scope for wastewater treatment plants (WWTP) to consider not only water quality and cost, but also greenhouse gas (GHG) emissions and climate change calls for new tools to evaluate operational strategies/treatment technologies. The IWA Benchmark Simulation Model no. 2 (BSM2) has been widely used within the scientific community for the unbiased comparison of control strategies in wastewater treatment facilities. In this paper, the default set of BSM models is extended with a set of comprehensive dynamic approaches that estimate the most significant on-site (secondary treatment, sludge processing) and off-site (net energy use, embedded chemicals, sludge disposal) sources of GHG emissions. The case study presented here calculates and discusses the changes in the effluent quality (EQI) and operational cost (OCI) indices and the formation of carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O) when modifying the percentage of total suspended solids (TSS) removal efficiency in the primary clarifier (PRIM). Simulations show that high PRIM efficiency decreases the quantity of TSS entering the activate sludge (AS) section leading to lower operational cost due to better energy recovery (and subsequent reduced GHG emissions) in the sludge line, but increases the overall N2O emissions due to the low C/N ratio as a trade-off. Overloading of the bioreactors as a result of poor PRIM performance: i) increases the biogenic CO2 emissions from BOD oxidation and biomass decay in the AS section; ii) increases off-site CO2 emissions due to higher energy demand during the nitrification stage; and, iii) reduces energy recovery from settled organics. The reported results emphasize the importance of a plant-wide approach and the need to consider the interactions between the different treatment units when evaluating the global warming potential (GWP) of a WWTP. Finally, the paper demonstrates the potential of using the proposed approach as a general model-based tool for determining the most sustainable WWTP operational strategies, which is essential in a water sector where climate change, energy and sustainability are key challenges to be tackled.